ACGS: Standardisation of variant interpretation and reports

Transcription

1 ACGS: Standardisation of variant interpretation and reports Sian Ellard South West NHS Genomic Medicine Centre Festival of Genomics, 31 st January 2018

2 Genome sequencing for clinical diagnosis ,000 Genomes Project Genome sequencing as an NHS test October 1 st 2018

3 Whole genome sequencing is (relatively) straightforward Variant interpretation is not

4 Genetic variants The human genome consists of 3 billion DNA bases that encode ~20,000 genes Each genome differs by 3-4 million variants Each individual has ~150 rare variants that are predicted to affect protein function (Lek et al Nature 2016 ExAC MAF<0.1%) There are many different types of variants e.g. missense, splicing, nonsense, small deletions, insertions, gene copy number changes and chromosome rearrangements

5 Quality improvement Innovation Standardisation The 100,000 Genomes Project is catalysing laboratory service transformation at pace and scale.

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7 New variant interpretation guidelines from USA Pathogenic Likely pathogenic (>90%) Uncertain significance Likely benign (<90%) Benign

8 Summary of evidence framework Richards et al 2015 Genetics in Medicine; Jarvik and Browning 2016 Am J Hum Genet

9 Rules for combining criteria to classify variants Pathogenic Likely pathogenic (>90%) Uncertain significance Likely benign (<90%) Benign

10 Variant classification evidence

11 Assess the evidence for a variant across all patients for which information is available Publications Patient referred for testing Public/NHS databases Laboratory database

12 Assessing variant pathogenicity Search databases: HGMD Pro DECIPHER ClinVar Gene specific Google scholar Protein analysis: In vitro modelling Functional studies Animal models Clinical data: Muscle biopsy Nerve conduction studies Drug response Metabolic profile Biochemistry Immunology

13 Case example lethal fetal disorder POMGNT1 p.arg497gln/n POMGNT1 p.arg497gln/n Fetus 1 TOP 22/40 Rapidly progressing ventriculomegaly No DNA 2 Not homozygous Fetus 2 TOP 18/40 Rapidly progressing ventriculomegaly No genetic diagnosis POMGNT1 p.arg497gln/p.arg497gln Exome sequencing (23,244 genes) of parental DNA samples

14 Case example lethal fetal disorder Evidence: PM1, PM2, PP3, PP1 (1/7 need 1/8) One report of this variant on ClinVar database An to the Emory lab provides a key piece of evidence; the variant is homozygous in a patient with the characteristic phenotype Evidence: PM1, PM2, PP3, PS4_Supporting, PP4, PP1 (1/7 need 1/8) MDT discussion (referring clinical geneticist and lab scientists with input from external experts) concludes that variant is likely pathogenic

15 Putting the ACMG guidelines into practice Principles Use the guidelines as a framework to determine whether there is sufficient evidence to classify the variant as likely pathogenic or likely benign Incorporate clinical data (functional and gene specific phenotype) Use your professional judgement

16 Variant classification and interpretation workshop 4th November 2016 Introduction to ACMG guidelines Early adopters experience Aligning CNV classification Integrating clinical phenotype and interpretation

17 Improving the quality of variant interpretation for clinical diagnosis Train the trainers: February 28 th Regional centres represented Emma Baple

18 Monthly WebEx for regional trainers Two cases per month circulated Submit classifications before meeting Review cases at meeting Produce worked case examples On-line resource (Jostle) Share ideas for local implementation Cases

19 Disease-specific subgroups Cancer Cardiac Familial hypercholesterolaemia

20 ACGS guidelines published October 2017 PS3 (Strong) Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product. Functional studies can include in vitro functional assays (eg. reporter gene assays for transcription factors), measurement of proteins in vivo (eg. biochemical tests on patient samples) mrna analysis for suspected splicing variants and other investigations where the results are pathognomonic of a specific single genetic cause of a disorder. See Table 2 for a list of examples.

21 Functional domain or mutation hot spot? PM1 (Moderate) Located in a mutational hot spot and/or critical and well-established functional domain (e.g., active site of an enzyme) without benign variation. Plot functional domains, ExAC variants, HGMDPro/ClinVar/LOVD etc variants and Consurf/conservation plots to show reported pathogenic variants, proxy population and benign variants and amino acid conservation for a region of a gene. PM1 Plot for SOX10 p.(ala132val)

22 NOTCH2 p.arg1895his variant in patient with?alagille syndrome

23 The ACMG guidelines are evolving

24 Developing a standardised report template Working group: Steve Abbs, Ed Blair, Diana Eccles, Sandi Deans, Sian Ellard (Chair), Helen Firth, David Gokale, Lucy Jenkins, Tracy Lester, Dom McMullan, Sian Morgan, Bill Newman, Chris Patch and Richard Scott Aim To develop an improved, standardised report template for clinical genomic tests performed in UK laboratories. The standardised report template will communicate the results of clinical genomic tests in a format that facilitates understanding of the results by a specialist or non-specialist healthcare professional and the patient or their family.

25 F-shaped reading pattern 20-30% text actually read

26 Standard report template

27 Standard report template Appendix Variant classification and MDT meeting summary form

28 Standard report template

29 Thank you ClinGen team (USA) All the UK regional trainers Reporting template working group members